Abstract

Endometrial cancer is the most commonly diagnosed cancer of the female reproductive tract in developed countries. Through genome-wide association studies (GWAS), we have previously identified eight risk loci for endometrial cancer. Here, we present an expanded meta-analysis of 12,906 endometrial cancer cases and 108,979 controls (including new genotype data for 5624 cases) and identify nine novel genome-wide significant loci, including a locus on 12q24.12 previously identified by meta-GWAS of endometrial and colorectal cancer. At five loci, expression quantitative trait locus (eQTL) analyses identify candidate causal genes; risk alleles at two of these loci associate with decreased expression of genes, which encode negative regulators of oncogenic signal transduction proteins (SH2B3 (12q24.12) and NF1 (17q11.2)). In summary, this study has doubled the number of known endometrial cancer risk loci and revealed candidate causal genes for future study.

Details

Title
Identification of nine new susceptibility loci for endometrial cancer
Author
Tracy A O’Mara 1   VIAFID ORCID Logo  ; Glubb, Dylan M 1   VIAFID ORCID Logo  ; Amant, Frederic 2 ; Annibali, Daniela 2   VIAFID ORCID Logo  ; Ashton, Katie 3 ; Attia, John 4   VIAFID ORCID Logo  ; Auer, Paul L 5 ; Beckmann, Matthias W 6 ; Black, Amanda 7 ; Bolla, Manjeet K 8 ; Brauch, Hiltrud 9   VIAFID ORCID Logo  ; Brenner, Hermann 10 ; Brinton, Louise 7 ; Buchanan, Daniel D 11   VIAFID ORCID Logo  ; Burwinkel, Barbara 12 ; Chang-Claude, Jenny 13 ; Chanock, Stephen J 7 ; Chu, Chen 14 ; Chen, Maxine M 15 ; Cheng, Timothy H T 16 ; Clarke, Christine L 17 ; Clendenning, Mark 18 ; Cook, Linda S 19 ; Couch, Fergus J 20 ; Cox, Angela 21 ; Crous-Bous, Marta 22 ; Czene, Kamila 23 ; Day, Felix 24   VIAFID ORCID Logo  ; Dennis, Joe 8   VIAFID ORCID Logo  ; Depreeuw, Jeroen 25 ; Doherty, Jennifer Anne 26 ; Dörk, Thilo 27 ; Dowdy, Sean C 28 ; Dürst, Matthias 29 ; Ekici, Arif B 30 ; Fasching, Peter A 31   VIAFID ORCID Logo  ; Fridley, Brooke L 32 ; Friedenreich, Christine M 33   VIAFID ORCID Logo  ; Fritschi, Lin 34 ; Fung, Jenny 35 ; García-Closas, Montserrat 36 ; Gaudet, Mia M 37 ; Giles, Graham G 38 ; Goode, Ellen L 39 ; Gorman, Maggie 16 ; Haiman, Christopher A 40 ; Hall, Per 41 ; Hankison, Susan E 42 ; Healey, Catherine S 43 ; Hein, Alexander 6   VIAFID ORCID Logo  ; Hillemanns, Peter 27 ; Hodgson, Shirley 44 ; Hoivik, Erling A 45 ; Holliday, Elizabeth G 4 ; Hopper, John L 46 ; Hunter, David J 47 ; Jones, Angela 16 ; Krakstad, Camilla 45 ; Kristensen, Vessela N 48 ; Lambrechts, Diether 49 ; Loic Le Marchand 50 ; Liang, Xiaolin 51 ; Lindblom, Annika 52 ; Lissowska, Jolanta 53 ; Long, Jirong 54 ; Lu, Lingeng 55   VIAFID ORCID Logo  ; Magliocco, Anthony M 56 ; Martin, Lynn 57   VIAFID ORCID Logo  ; McEvoy, Mark 58 ; Meindl, Alfons 59 ; Michailidou, Kyriaki 60   VIAFID ORCID Logo  ; Milne, Roger L 61   VIAFID ORCID Logo  ; Mints, Miriam 62 ; Montgomery, Grant W 63   VIAFID ORCID Logo  ; Nassir, Rami 64 ; Olsson, Håkan 65 ; Orlow, Irene 51 ; Otton, Geoffrey 66 ; Palles, Claire 16 ; Perry, John R B 24 ; Peto, Julian 67 ; Pooler, Loreall 40 ; Prescott, Jennifer 68 ; Proietto, Tony 66 ; Rebbeck, Timothy R 69 ; Risch, Harvey A 55 ; Rogers, Peter A W 70 ; Rübner, Matthias 71 ; Runnebaum, Ingo 29 ; Sacerdote, Carlotta 72 ; Sarto, Gloria E 73 ; Schumacher, Fredrick 74 ; Scott, Rodney J 75 ; Setiawan, V Wendy 40 ; Shah, Mitul 43 ; Sheng, Xin 40 ; Xiao-Ou, Shu 54 ; Southey, Melissa C 76 ; Swerdlow, Anthony J 77 ; Tham, Emma 78 ; Trovik, Jone 45 ; Turman, Constance 15 ; Tyrer, Jonathan P 43 ; Vachon, Celine 79 ; David VanDen Berg 40 ; Vanderstichele, Adriaan 80 ; Wang, Zhaoming 7 ; Webb, Penelope M 81   VIAFID ORCID Logo  ; Wentzensen, Nicolas 7 ; Werner, Henrica M J 45 ; Winham, Stacey J 82 ; Wolk, Alicja 83   VIAFID ORCID Logo  ; Xia, Lucy 40 ; Yong-Bing, Xiang 84 ; Yang, Hannah P 7 ; Yu, Herbert 50   VIAFID ORCID Logo  ; Zheng, Wei 54   VIAFID ORCID Logo  ; Pharoah, Paul D P 85   VIAFID ORCID Logo  ; Dunning, Alison M 43 ; Kraft, Peter 47 ; De Vivo, Immaculata 22 ; Tomlinson, Ian 86   VIAFID ORCID Logo  ; Easton, Douglas F 85   VIAFID ORCID Logo  ; Spurdle, Amanda B 1 ; Thompson, Deborah J 8   VIAFID ORCID Logo 

 Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia 
 Department of Obstetrics and Gynecology, University Hospitals KU Leuven, University of Leuven, Division of Gynecologic Oncology, Leuven, Belgium 
 John Hunter Hospital, Hunter Medical Research Institute, Newcastle, NSW, Australia; University of Newcastle, Centre for Information Based Medicine, Callaghan, NSW, Australia; University of Newcastle, Discipline of Medical Genetics, School of Biomedical Sciences and Pharmacy, Faculty of Health, Callaghan, NSW, Australia 
 John Hunter Hospital, Hunter Medical Research Institute, Newcastle, NSW, Australia; University of Newcastle, Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, Callaghan, NSW, Australia 
 Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; University of Wisconsin-Milwaukee, Zilber School of Public Health, Milwaukee, WI, USA 
 Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center ER-EMN, Erlangen, Germany 
 National Cancer Institute, Division of Cancer Epidemiology and Genetics, Bethesda, MD, USA 
 Department of Public Health and Primary Care, University of Cambridge, Centre for Cancer Genetic Epidemiology, Cambridge, UK 
 Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany; University of Tübingen, Tübingen, Germany; German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany 
10  German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany; Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany; Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany 
11  Department of Clinical Pathology, The University of Melbourne, Melbourne, VIC, Australia; The University of Melbourne, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, Melbourne, VIC, Australia; Genetic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, VIC, Australia; Victorian Comprehensive Cancer Centre, University of Melbourne Centre for Cancer Research, Parkville, VIC, Australia 
12  Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany; Molecular Epidemiology Group, C080, German Cancer Research Center (DKFZ), Heidelberg, Germany 
13  Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; University Medical Center Hamburg-Eppendorf, Cancer Epidemiology, University Cancer Center Hamburg (UCCH), Hamburg, Germany 
14  Epidemiology Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA 
15  Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA 
16  University of Oxford, Wellcome Trust Centre for Human Genetics and Oxford NIHR Biomedical Research Centre, Oxford, UK 
17  University of Sydney, Westmead Institute for Medical Research, Sydney, NSW, Australia 
18  Department of Clinical Pathology, The University of Melbourne, Melbourne, VIC, Australia; Victorian Comprehensive Cancer Centre, University of Melbourne Centre for Cancer Research, Parkville, VIC, Australia 
19  University of New Mexico, University of New Mexico Health Sciences Center, Albuquerque, NM, USA; Department of Cancer Epidemiology and Prevention Research, Alberta Health Services, Calgary, AB, Canada 
20  Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA 
21  Department of Oncology and Metabolism, University of Sheffield, Sheffield Institute for Nucleic Acids (SInFoNiA), Sheffield, UK 
22  Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Medicine, Harvard Medical School, Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, MA, USA 
23  Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden 
24  University of Cambridge, MRC Epidemiology Unit, School of Clinical Medicine, Cambridge, UK 
25  Department of Obstetrics and Gynecology, University Hospitals KU Leuven, University of Leuven, Division of Gynecologic Oncology, Leuven, Belgium; VIB, Vesalius Research Center, Leuven, Belgium; Department of Human Genetics, University of Leuven, Laboratory for Translational Genetics, Leuven, Belgium 
26  Cancer Research Huntsman Cancer Institute Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA 
27  Gynaecology Research Unit, Hannover Medical School, Hannover, Germany 
28  Department of Obstetrics and Gynecology, Mayo Clinic, Division of Gynecologic Oncology, Rochester, MN, USA 
29  Department of Gynaecology, Jena University Hospital - Friedrich Schiller University, Jena, Germany 
30  Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Institute of Human Genetics, University Hospital Erlangen, Erlangen, Germany 
31  Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center ER-EMN, Erlangen, Germany; Department of Medicine, University of California at Los Angeles, David Geffen School of Medicine, Division of Hematology and Oncology, Los Angeles, CA, USA 
32  Department of Biostatistics, Kansas University Medical Center, Kansas City, KS, USA 
33  Department of Cancer Epidemiology and Prevention Research, Alberta Health Services, Calgary, AB, Canada 
34  Curtin University, School of Public Health, Perth, WA, Australia 
35  University of Queensland, Institute for Molecular Bioscience, Brisbane, QLD, Australia 
36  National Cancer Institute, Division of Cancer Epidemiology and Genetics, Bethesda, MD, USA; Institute of Cancer Research, Division of Genetics and Epidemiology, London, UK 
37  American Cancer Society, Epidemiology Research Program, Atlanta, GA, USA 
38  The University of Melbourne, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, Melbourne, VIC, Australia; Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, VIC, Australia; Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, Australia 
39  Department of Health Science Research, Mayo Clinic, Division of Epidemiology, Rochester, MN, USA 
40  Department of Preventive Medicine, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA 
41  Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Oncology, South General Hospital, Stockholm, Sweden 
42  Department of Medicine, Harvard Medical School, Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, MA, USA; Department of Biostatistics and Epidemiology, University of Massachusetts, Amherst, Amherst, MA, USA 
43  Department of Oncology, University of Cambridge, Centre for Cancer Genetic Epidemiology, Cambridge, UK 
44  Department of Clinical Genetics, St George’s, University of London, London, UK 
45  Department of Clinical Science, University of Bergen, Centre for Cancer Biomarkers, Bergen, Norway; Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway 
46  The University of Melbourne, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, Melbourne, VIC, Australia 
47  Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA 
48  Department of Cancer Genetics, Oslo University Hospital, Radiumhospitalet, Institute for Cancer Research, Oslo, Norway; University of Oslo, Institute of Clinical Medicine, Faculty of Medicine, Oslo, Norway; Department of Clinical Molecular Biology, University of Oslo, Oslo University Hospital, Oslo, Norway 
49  Department of Human Genetics, University of Leuven, Laboratory for Translational Genetics, Leuven, Belgium; VIB, VIB Center for Cancer Biology, Leuven, Belgium 
50  Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA 
51  Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA 
52  Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden 
53  Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Cancer Center-Oncology Institute, Warsaw, Poland 
54  Department of Medicine, Vanderbilt University School of Medicine, Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Nashville, TN, USA 
55  Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA 
56  Department of Anatomic Pathology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA 
57  University of Birmingham, Institute of Cancer and Genomic Sciences, Birmingham, UK 
58  University of Newcastle, Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, Callaghan, NSW, Australia 
59  Department of Gynecology and Obstetrics, Ludwig-Maximilians University of Munich, Munich, Germany 
60  Department of Public Health and Primary Care, University of Cambridge, Centre for Cancer Genetic Epidemiology, Cambridge, UK; Department of Electron Microscopy/Molecular Pathology, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus 
61  The University of Melbourne, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, Melbourne, VIC, Australia; Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, VIC, Australia 
62  Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden 
63  Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; University of Queensland, Institute for Molecular Bioscience, Brisbane, QLD, Australia 
64  Department of Biochemistry and Molecular Medicine, University of California Davis, Davis, CA, USA 
65  Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund, Sweden 
66  University of Newcastle, School of Medicine and Public Health, Callaghan, NSW, Australia 
67  Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK 
68  Department of Medicine, Harvard Medical School, Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, MA, USA 
69  Harvard T.H. Chan School of Public Health, Boston, MA, USA; Dana-Farber Cancer Institute, Boston, MA, USA 
70  Department of Obstetrics and Gynaecology, University of Melbourne, Royal Women’s Hospital, Gynaecology Research Centre, Parkville, VIC, Australia 
71  Department of Gynaecology and Obstetrics, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, University Hospital Erlangen, Erlangen, Germany 
72  Center for Cancer Prevention (CPO-Peimonte), Turin, Italy; Human Genetics Foundation (HuGeF), Turino, Italy 
73  Department of Obstetrics and Gynecology, University of Wisconsin, School of Medicine and Public Health, Madison, WI, USA 
74  Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA 
75  John Hunter Hospital, Hunter Medical Research Institute, Newcastle, NSW, Australia; University of Newcastle, Centre for Information Based Medicine, Callaghan, NSW, Australia; University of Newcastle, Discipline of Medical Genetics, School of Biomedical Sciences and Pharmacy, Faculty of Health, Callaghan, NSW, Australia; John Hunter Hospital, Division of Molecular Medicine, Pathology North, Newcastle, NSW, Australia 
76  Department of Clinical Pathology, The University of Melbourne, Melbourne, VIC, Australia; Monash University, Precision Medicine, School of Clinical Sciences at Monash Health, Clayton, VIC, Australia 
77  Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK; Division of Breast Cancer Research, The Institute of Cancer Research, London, UK 
78  Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Karolinska Institutet, Clinical Genetics, Stockholm, Sweden 
79  Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA 
80  Department of Obstetrics and Gynaecology, University Hospitals Leuven, Division of Gynecologic Oncology, Leuven Cancer Institute, Leuven, Belgium 
81  Department of Population Health, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia 
82  Department of Health Science Research, Mayo Clinic, Division of Biomedical Statistics and Informatics, Rochester, MN, USA 
83  Department of Environmental Medicine, Karolinska Institutet, Division of Nutritional Epidemiology, Stockholm, Sweden 
84  Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, State Key Laboratory of Oncogene and Related Genes, Shanghai, China 
85  Department of Public Health and Primary Care, University of Cambridge, Centre for Cancer Genetic Epidemiology, Cambridge, UK; Department of Oncology, University of Cambridge, Centre for Cancer Genetic Epidemiology, Cambridge, UK 
86  University of Oxford, Wellcome Trust Centre for Human Genetics and Oxford NIHR Biomedical Research Centre, Oxford, UK; University of Birmingham, Institute of Cancer and Genomic Sciences, Birmingham, UK 
Pages
1-12
Publication year
2018
Publication date
Aug 2018
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2086250969
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.